Salts of aryl-substituted amino alcohols and processes for their production



Patented Oct. 25, 1938 SALTS ARIEL-SUBSTITUTED AMINO AL- COHOLS ANDPROCESSES FOR THEIR PRO- DUCTION om Dalmer and Fritz von Werder,Darmstadt,

Germany, assignors to Merck & 00., Inc., Rahway, N. J., a corporation ofNew Jersey No Drawing. Original application September 15, 1934, SerialNo. 744,168. Patent No. 2,094,000. Divided and this application February27, 1937, Serial No. 128,160. In Germany September 22,

s Claims. (01. 260-501) This is a division of application Serial No.744,168 filed September 15, 1934.

This invention relates to coumarin-carboxylic acid salts of certainaryl-substituted amino alcohols of the type of ephedrine, its homologuesand derivatives having the general formula V (R=phenyl or substitutedphenyl, X, Y, Z= hydrogen or alkyl) as will further appear, and toprocesses for their production.

Although the well-known sympathomimetically-acting bases of theephedrine group exhibit properties which are medicinally valuable, suchas deepened respiration and increased blood pres- 20 sure, they alsomanifest undesirable, irritating by-effects which, in relatively largedoses, lead to clonicotonic spasms.

However, it has been found that such compounds, when combined withcoumarin-B-car- 25 boxylic acid, will not show unfavorable by-effects tosuch a pronounced degree. Nothing has hitherto been known as to thephysiological action of coumarin-B-carboxylic acid. It was, therefore,not to be anticipated that the new compounds 30 formed by combining thisacid with bases of the group mentioned, would manifest, instead of astimulating effect, a sedative action which is characterized by lethargyand slight narcosis, and

which is increased when the compounds are'ad- 35 ministered inrelatively large doses.

Furthermore, it is noteworthy that the combination of racemictrans-ephedrine with coumarin-carboxylie acid is effective inconsiderably smaller doses than is racemic trans-ephedrine alone. Thetherapeutic latitude, that is, the relationship of fatal dose toeffective limit, which in racemic trans-ephedrine combined withcoumarin-carboxylic acid brings about deepened 45 respiration and slightnarcosis, and in transephedrine alone brings about slight irritativespasms, is much greater with the former and, therefore, more favorablewith it than with the known racemic trans-ephedrine.

50 The following table shows the values which resire to limit ourselvesto the specific embodiments sulted from pharmacological experiments onmice: M 7

Method of application gzgg figgl 5 Racemic tram-ephedrine salt of canmarin-carbozylic acid q/a- Mg/g. Intravenous 0.01 0. 05 1o Subcutaneous0. 025 0. 1 Per m 0. 025 0.25

Racemic trans-ephedrine Intravenous 0. 1 0. 175 Snhmrfanenus 0. 5 1. 0Per as V 1.0 1. 5

wherein R is a phenyl or substituted phenyl group, and X, Y, and Z arehydrogen or alkyl 40 I groups.

The various steps of the process are set forth in the accompanyingexamples. Obviously, these steps may be modified considerably withrespect to their order and number and the specific materials used,without departing from the spirit of the invention substantially asdescribed and claimed, and it is understood that we do not deshown.

Example I 190 parts by weight of coumarin-S-carboxylic acid aredissolved in 3600 parts by volume of acetone, and 165 parts by weight ofracemic trans-ephedrine are dissolved in 1650 parts by volume ofacetone. Both solutions are combined while hot and kept boiling on thereflux for half an hour. While boiling, the salt beginsto separate andafter cooling is filtered oil by suction and washed out with cooledacetone. lization from water, 297 parts by weight of pure salt areobtained in the form of finely formed large crystals, having a meltingpoint of 196.

Example 11' 825 parts of l-ephedrine and 950 parts of 0011-marin-S-carboxylic acid are finely pulverized and thoroughly mixed. Themixture is carefully melted in an oil bath at 140. The molten mass aftercooling is dissolved in a small amount of alcohol; from this solutionthe salt is precipitated by adding a three-fold volume of ether, and

is finely recrystallized from acetone. The product is obtained in theform of colorless needles,- which after drying melt at 136- 137. 100parts of water at 20 dissolve"8.29 parts of this salt.

Example III a crystalline pulp is precipitated. The whole is boiled fora short time under refluxing. The crystallization product. isolatedafter cooling, is recrystallized from alcohol and is obtained in theform of fine colorless needles having a melting point of 184.

Example IV V 7 By mixing a solution of 11 parts 'by weight of1-p-aminophenol-2 metlr1ylamino-propanol in 100 parts by volume ofacetone with a solution of 11.6 parts by weight of coumarin-B-carboxylicacid in 270 parts by volume of acetone, heat is liberated. Immediatelyfollowing, crystallization of the formed salt sets in, and the salt isseparated after cooling and recrystallized from methanol. the form of.leaves, having a melting point or 182.

Example V 380 parts of coumarin-B-carboxylic acid are dissolved in alarge excessof acetone. To'the solution, heated to 40, 366 parts ofl-adrenaline base are added in small amounts under constant stirring.After all has been added, the stirring is continued for another hour andthe temperature slowly increased to 50. Finally the reaction containeris closed tightly andleft standing for 24 hours at room temperature.Thereafter, the unchanged l-adrenaline base is filtered off by suctionand washed out with acetone. From the concentrated filtrate the desiredsalt is obtained, having a melting point of 162163. I

Example VI 40,000 parts by volume of hot chloroform are poured over 34parts by weight of l-p-hydroxyphenyl-Z-methylamino-ethan-1-01. After.adding a solution of 38.8 parts by weight of cou- By recrystal- 16 partsby weightof salt are obtained in barium salt of coumarino-3-carboxylicacid are suspended in 70 parts of water without previous :1 drying andshaken with a solution of 2 parts by weight l-ephedrinesulfate for sometime, heating the mixtureslightly. The change in the outer appearance ofthe precipitate indicates the end of the cross-reaction; the copiousbarium salt of coumarin-B-calrboxylic acid changes into the finelypowdered, rapidly sedimenting bariumsulfate. The precipitate is thenfiltered ofi and the solution evaporated to dryness. By recrystallizingthe residue from acetone the pure l-ephedrine saltofTcoumarin-ii-carboxylic acid is obtained, having a melting point of137.

. We claim as our-invention:

1. A coumarin-3-carboxylicacid salt of a substituted amino alcohol ofthe group consisting of l-adrenaline, l-p-aminophenyl-Z-methylaminopropanol, and l-1-phenyl-2-methyl aminoethan-l-oh v I 2. Thecoumarin-3-c'arboxylic acid salt of l-adrenaline.

3. The coumarin-3-carboxylic-acid salt of 1-p-aminophenyl2-methylarnino-propanol.

4. The coumarin-B-carboxylic acid salt ofl-1-phenyl-2-methylamino-ethan-l-ol. 7 Y -5. A process. fortheproductionof a coumarin- 3-carboxylic acid salt of a'substituted amino alcohol ofthe group consisting of l-adrenaline,1-p-aminophenyl-2-methylamino-propanol and l 1 -phenyl 2methylaminoethan- 1-ol which comprises reacting upon said alcohol withcoumarin 3-carboxylic acid.

6. 'A process for the production of. a coumarin- B-carboxylic acid saltof a substituted amino alcohol of the group consisting'of l-adrenaline,1-p-aminophenyl-2-methylamino-propanol, and l- 1 phenyl 2methylamino-ethan- 1-ol which comprises mixing said acid and saidalcohol in solution in aninert aliphatic solvent, and thereaftercrystallizing out said salts. 7. A process for the production of acoumarin- B carboxylic acid salt of a substituted amino alcohol of thegroup consisting of l-adrenaline,1-p-aminophenyl-2-methylamino-propanol, and l- 1 phenyl 2methylamino-ethan-1-ol which comprises melting saidacid and alcoholtogether, cooling the resultant molten mass and dissolving in alcoholprecipitating the salt by the addition of ether, and thereaftercrystallizing said salt from acetone. 7

8. A process for the production of a coumarin- 3-carboxylic acid salt ofa substituted amino alcohol of the group consisting of l-adrenaline,1-paminophenyl-2-methylamino-propanol, and l-1-phenyl-2-methylamino-ethan-1-01 which comprises cross reaction insolution between a salt of coumarin-3-carboxylic acid and a salt of asubstituted amino alcohol.

\ a O'I'IO DALMER.

FRITZ VON WERDER.

